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Ann Thorac Surg 1996;62:670-674
© 1996 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Defining the Role of Aprotinin in Heart Transplantation

Thomas W. Prendergast, MD, Satoshi Furukawa, MD, A. James Beyer, III, MD, Howard J. Eisen, MD, James B. McClurken, MD, Valluvan Jeevanandam, MD

Division of Cardiothoracic Surgery, University of Kansas Medical Center, Kansas City, Kansas, and Sections of Cardiothoracic Surgery and Cardiology, Temple University Health Sciences Center, Philadelphia, Pennsylvania


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background. Heart transplantation is associated with excessive bleeding due to recipient coagulopathy, frequent need for reoperative median sternotomy, and prolonged cardiopulmonary bypass. Aprotinin reduces bleeding and the inflammatory response after cardiopulmonary bypass, but there are concerns about efficacy and side effects.

Methods. To determine the role of aprotinin in primary and reoperative sternotomy heart transplantation, we studied 70 patients undergoing heart transplantation between August 1993 and October 1994. Thirty-eight undergoing primary sternotomy for heart transplantation and receiving no aprotinin were randomized to group A (n = 20); patients in group B (n = 18) received the full recommended dose. Similarly, 32 patients undergoing reoperative heart transplantation were randomized to group C (n = 16), receiving no aprotinin, and to group D (n = 16), receiving aprotinin at the full recommended dose. All patients received the same immunosuppression regimen. Similarities in the groups included recipient age, weight, preoperative hemodynamic indices, creatinine, creatinine clearance, platelet count, hemoglobin, percentage receiving warfarin, prothrombin time, partial thromboplastin time, cardiopulmonary bypass time, and creatinine level at 48 hours.

Results. There were no significant differences postoperatively between groups A and B. Differences (p < 0.05) 24 hours postoperatively between groups C and D, respectively, included: total blood product requirement (5.9 ± 3.8 versus 3.6 ± 2.0 U), total fluid balance (+752 ± 300 versus -250 ± 185 mL), chest tube drainage (894 ± 120 versus 526 ± 95 mL), alveolar-arterial O2 difference (120.4 ± 45.9 versus 95.5 ± 33.5), and pulmonary artery mean pressures (28.2 ± 4.6 versus 21.1 ± 3.5 mm Hg).

Conclusions. Aprotinin decreases bleeding after reoperative heart transplantation without renal dysfunction. Decreased inflammation is manifested as reduced fluid requirement and improved pulmonary and right heart function, which benefit patients during the posttransplantation period. Aprotinin at recommended doses is effective and safe for patients undergoing reoperative heart transplantation.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Aprotinin is a nonspecific serine protease inhibitor derived from bovine lung. This drug was first used in clinical practice in 1953 as an inhibitor of trypsin and chymotrypsin in the treatment of pancreatitis [1]. The drug was first reported in cardiac surgery during the 1960s, when several groups used aprotinin to treat fibrinolysis occurring during cardiopulmonary bypass (CPB) [2, 3]. In the 1980s, new studies demonstrated that aprotinin reduces the inflammatory response and bleeding after CPB [4, 5]. Since these initial reports, the use of aprotinin has become increasingly common in cardiac surgery. Current theory holds that aprotinin inhibits the action of plasmin, thereby preserving platelet membrane receptors and decreasing the accumulation of fibrin degradation products, which interfere with platelet aggregation and fibrin cross-linking [6]. In addition, aprotinin blocks the action of kallikrein, thereby decreasing contact activation of the intrinsic coagulation system [7]. Through these multiple pathways, aprotinin protects platelet function, suppresses the fibrinolytic pathway, and decreases inflammation in patients undergoing CPB, thereby improving hemostasis in this group. Although the ultimate place of aprotinin in the armamentarium of hemostatic agents used during cardiac operations remains uncertain, the indications for use of this drug are becoming clearer. Because cardiac transplantation patients often sustain substantial intraoperative blood loss secondary to reoperative sternotomy, recipient coagulopathy, and prolonged CPB times, aprotinin therapy would seem to be ideal for this group of patients. However, because of concerns regarding efficacy and side effects, the role of aprotinin in cardiac transplantation remains undefined. This study was done to determine the role of aprotinin in heart transplantation (HT) and to define which patients would benefit from the use of this drug.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Seventy patients underwent HT between August 1, 1993 and October 31, 1994. Thirty-eight of these patients underwent primary sternotomy for HT and were prospectively randomized in a nonblinded fashion into two groups. Group A (n = 20) received no aprotinin; group B (n = 18) received aprotinin. Aprotinin (Trasylol; Bayer, Germany) was administered in a 1-mL test dose, followed by a 200-mL loading dose intravenously (IV); an additional 200 mL was given in the CPB circuit. The aprotinin was continued thereafter at 50 mL/h until the termination of operation. We intentionally avoided the use of desmopressin, tranexamic acid, and {epsilon}-aminocaproic acid in this group of patients. Similarly, 32 patients underwent reoperative sternotomy for HT. These patients were prospectively randomized in a nonblinded fashion into group C (n = 16), receiving no aprotinin, and group D (n = 16), receiving aprotinin as described previously. Once again, desmopressin, tranexamic acid, and {epsilon}-aminocaproic acid were avoided. All patients received 2 days of cytolic therapy followed by standard triple-drug immunosuppression. OKT3 induction therapy included a dose of 5 mg on CPB, followed by 5 mg IV per day for 2 days. Methylprednisolone was given on postoperative day 2 at a dose of 125 mg IV every 8 hours for 3 days, then tapered beginning at a dose of methylprednisolone of 100 mg IV per day. Azathioprine was administered on postoperative day 2 at a dose of 2 mg/kg per day. Cyclosporin A was given in divided doses twice per day beginning at 5 mg/kg per day to achieve a blood level of 300 ng/mL by whole blood radioimmunoassay (Abbott TDX). Preoperatively, neither groups A and B nor groups C and D differed significantly in recipient age, weight, preoperative hemodynamic indices, serum creatinine, creatinine clearance, platelet count, hemoglobin, prothrombin time, partial thromboplastin time, or percentage of patients receiving warfarin (Tables 1, 2GoGo).


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  		Table 1. . Preoperative Characteristics of Patients Undergoing Primary Heart Transplantation
 

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  		Table 2. . Preoperative Characteristics of Patients Undergoing Reoperative Heart Transplantation
 
Groups were compared with regard to CPB times, alveolar-arterial gradient at 1 hour after CPB, fraction of inspired oxygen required at 24 hours postoperatively, alveolar-arterial gradient at 24 hours postoperatively, and days of mechanical ventilatory assistance. An analysis of blood product requirements included the total number of units transfused along with itemized transfusions of packed red blood cells, fresh frozen plasma, and platelets. The mean hemoglobin level at 24 hours postoperatively was recorded, along with the serum creatinine level at 24 and 72 hours postoperatively. Total chest tube drainage and net fluid balance were recorded at 24 hours postoperatively. Hemodynamic indices were compared at 24 hours postoperatively and included analysis of mean systemic blood pressure, mean pulmonary artery pressure, and mean cardiac index. All results are reported as mean values for each group ± standard deviation. Results were analyzed using an unpaired Student's t test, with significance considered at p less than 0.05.


   Results
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 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
As seen in Table 3Go, analysis of primary sternotomy HT patients demonstrated no significant differences between patients treated with aprotinin (group B) and those treated without aprotinin (group A). Blood product requirement was minimal in both groups, with no reduction due to aprotinin.


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  		Table 3. . Results of Primary Heart Transplantation With and Without Aprotinin
 
There were no significant differences in CPB times between the reoperative groups (Table 4Go). However, the aprotinin-treated reoperative patients (group D) appeared to have an improved alveolar-arterial gradient at 1 hour after CPB (p = 0.06) and a statistically significant improvement in alveolar-arterial gradient at 24 hours postoperatively (p < 0.05). There were no significant differences in inspired oxygen fraction requirements or days of mechanical ventilatory assistance between groups C and D.


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  		Table 4. . Results of Reoperative Heart Transplantation With and Without Aprotinin
 
Aprotinin-treated reoperative patients (group D) required significantly less total blood products than the non-aprotinin-treated reoperative patients (group C) (3.4 versus 9.2 U; p < 0.03). As seen in Table 4Go, group D patients received less packed red blood cells, less fresh frozen plasma, and fewer platelet transfusions than group C patients. Neither group appeared to have been "overtransfused," as both groups had a mean hemoglobin level of 8.8 mg/dL at 24 hours postoperatively. Each group had a similar hematologic profile (prothrombin time, partial thromboplastin time, and platelet count) 24 hours postoperatively.

Renal function did not differ significantly between groups. Groups C and D had similar mean serum creatinine levels on postoperative day 1 (1.3 versus 1.4; p = not significant) and postoperative day 3 (1.8 versus 1.9; p = not significant).

Group D patients had a more favorable chest tube drainage pattern and net fluid balance than group C (see Table 4Go). The mean chest tube output for group C versus group D at 24 hours postoperatively was 894 versus 526 mL, respectively (p < 0.03). The mean net fluid balance for group C and group D at 24 hours postoperatively was +752 and -250 mL, respectively (p < 0.02).

The overall hemodynamic performance between group C and group D did not differ significantly with regard to mean postoperative blood pressure or cardiac index (see Table 4Go). However, group D had significantly lower mean pulmonary artery pressures (21 ± 3.4 mm Hg) than group C (28 ± 4.6 mm Hg) (p < 0.05). Accordingly, group D had a higher mean cardiac index than group C (3.1 versus 2.7 mL • min-1 • m-2), although this was not statistically significant.


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Cardiopulmonary bypass is widely recognized as a frequent cause of coagulopathy in patients undergoing heart operations. Although it is likely that the cause of this coagulopathy is multifactorial, many investigators believe that CPB-induced platelet dysfunction is one of the primary causes of postoperative bleeding in this group of patients [8]. Fibrinolysis, a component of the hemostatic response triggered by CPB, is also a primary cause of bleeding secondary to extracorporeal circulation. Fibrinolysis causes bleeding because of a block in the coagulation cascade. During fibrinolysis, platelet receptors bind fibrin degradation products instead of fibrinogen. This inappropriate bonding leads to faulty platelet aggregation and therefore decreased platelet function [6]. At the same time, plasmin, the enzyme that initiates fibrinolysis, is a direct inhibitor of platelet function. It has been suggested that the direct inhibitory effect of plasmin on platelets stems from the ability of plasmin to degrade platelet membrane receptors including glyco-protein IIb, Von Willebrand factor, and the platelet fibrinogen receptor [6]. Adelman and co-workers [9] demonstrated that in the presence of plasmin, Von Wilebrand factor and platelet function decrease in a parallel fashion. Other workers showed a similar decrease in the platelet receptor IIb/IIc complex during CPB and postulated that this decrease was responsible for the poor platelet function observed in their study [10]. On the other hand, Orchard and co-workers [11] found no change in the levels of platelet membrane receptors when plasmin was administered to patients undergoing CPB. Thus, fibrin degradation products and perhaps plasmin combine to interfere with platelet function during CPB. Aprotinin helps with hemostasis by reducing the inflammatory ravages of CPB [7].

Aprotinin preserves platelet function during CPB by inhibiting the enzyme plasmin. Aprotinin blocks plasmin by two mechanisms. First, the drug inhibits kallakrein, which is partially responsible for converting plasminogen to plasmin [12]. Second, it directly inhibits the action of plasmin itself [12]. Inhibition of plasmin blocks the proposed inhibitory effects of this enzyme on platelet membrane receptors. In addition, inhibiting plasmin reduces CPB-induced fibrinolysis, thereby decreasing the amount of fibrin degradation products and their detrimental effects on platelet function.

The clinical significance of this improved hemostasis is manifested by a reduction in both total chest tube output and the need for blood transfusion among reoperative HT patients receiving aprotinin therapy. These findings correlate well with those of two other small series in which aprotinin appeared to result in a reduction of homologous blood transfusion requirements [13, 14]. Although postoperative chest tube output was considerable in reoperative patients, aprotinin did significantly decrease chest tube output in group D patients in our series. The benefits of aprotinin were also evident in the reduced transfusion requirements of group D versus group C patients. Although aprotinin did not eliminate the need for blood transfusions, it did substantially reduce the number of transfusions required in the treated group. This reduction in transfusions may correlate with a decreased risk for transfusion-associated infections (eg, cytomegalovirus). Similarly, this reduction in transfusions may result in less propensity toward humoral rejection [15]. The reductions in bleeding and transfusion requirements are also reflected in the improved net fluid balance at 24 hours among the patients treated with aprotinin. Overall, patients in group D were in negative fluid balance 24 hours postoperatively, whereas group C patients maintained a positive fluid balance.

The pulmonary status of group D patients was also better than that of their group C counterparts. This improvement was probably the result not only of the improved fluid balance in group D, but also of the antiinflammatory effects of aprotinin. These effects translated into an improved alveolar-arterial gradient and significantly lower mean pulmonary artery pressures. A commensurate improvement in right heart hemodynamic indices would be expected to accompany this decrease in mean pulmonary artery pressure, an advantage particularly helpful to avoid the dreaded complication of early right heart failure in patients with pulmonary hypertension.

Despite concerns that renal function is impaired in patients receiving aprotinin [16], we concur with others that there was no evidence of additional renal dysfunction in our patients who received aprotinin. Preoperative creatinine level and creatinine clearance, as well as creatinine 24 and 72 hours postoperatively, were similar in groups C and D. It is important to note, however, that patients included in this study received cytolytic therapy preoperatively and did not receive cyclosporin until postoperative day 2. Thus, no patients received aprotinin and cyclosporin simultaneously. Earlier pilot experience at our institution demonstrated that when cytolytic therapy was abandoned and cyclosporin as well as aprotinin were administered in the immediate postoperative period, renal dysfunction did increase. As a result, we now begin cyclosporin therapy on postoperative day 3 and have noticed no significant increase in renal dysfunction in reoperative patients receiving aprotinin. With this protocol, aprotinin does not appear to cause increased renal dysfunction compared with patients who do not receive aprotinin. This is particularly reassuring in transplant recipients who have a propensity for renal impairment due to the use of multiple nephrotoxins. Thus, aprotinin decreases bleeding after HT without increased renal dysfunction. In addition, we perceived no other complications referable to the use of aprotinin.

There did not appear to be any particular advantage to the use of aprotinin in patients undergoing primary sternotomy for cardiac transplantation. Aprotinin did not appear to improve the results regarding transfusions, pulmonary function, or hemodynamic function. The inability of aprotinin to significantly improve the results in patients undergoing primary HT may be due to the fact that bleeding is not a particular problem in this group of patients. Patients undergoing primary sternotomy generally have shorter CPB times and less bleeding than their reoperative counterparts, which makes improvement in hemostasis more difficult to demonstrate. On the other hand, there was no particular disadvantage associated with the use of aprotinin in this patient population.

Patients undergoing reoperative HT are at increased risk for bleeding secondary to repeat sternotomy and prolonged CPB times. Aprotinin decreases bleeding and inflammation after CPB by several mechanisms. Decreases in inflammation and bleeding in reoperative patients receiving aprotinin are manifested by decreased chest tube output and transfusion requirements as well as improved net fluid balance, pulmonary function, and right heart function. All of these effects benefit these patients during the immediate posttransplantation period. Therefore, aprotinin is recommended for the subset of patients undergoing reoperative HT.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 
Presented at the Poster Session of the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.

Address reprint requests to Dr Prendergast, Division of Cardiothoracic Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160-7373.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Frey EK. On the treatment of pancreatitis. Therapiewoche 1953;13–14:323.
  2. Tice DA, Worth MH, Clausse RH, Reed GH. The inhibition of trasylol of fibrinolytic activity associated with cardiovascular operations. Surg Gynecol Obstet 1964;119:71–4.
  3. Mammen EF. Natural proteinase inhibitors in extracorporeal circulation. Ann NY Acad Sci 1968;146:754–62.[Medline]
  4. Van Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 1987;44:640–5.[Abstract]
  5. Royston D, Taylor KM, Bidstrup BP, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289–91.[Medline]
  6. Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993; 55:1033–41.[Abstract]
  7. Havel M, Teufelsbauer H, Knobl P, et al. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J Thorac Cardiovasc Surg 1991;101:968–72.[Abstract]
  8. Blauhut B, Gross C, Necek S, Doran JE, Spath P, Lundsgaard-Hansen P. Effects of high dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;101:958–67.[Abstract]
  9. Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood 1985;65:32–40.[Abstract/Free Full Text]
  10. Dechavanne M, Ffrench M, Pages J, et al. Significant reduction in the binding of a monoclonal antibody (LYP 18) directed against the GP IIb/IIIa glycoprotein complex to platelets of patients having undergone extracorporeal circulation. Thromb Haemost 1987;57:106–9.[Medline]
  11. Orchard WA, Goodchild CS, Prentice CRM, et al. Aprotinin reduces cardiopulmonary bypass-induced blood loss and inhibits fibrinolysis without influencing platelets. Br J Haematol 1993;85:533–41.[Medline]
  12. Van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CRH. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:788–97.[Abstract]
  13. Propst JW, Siegel LC, Feeley TW. Effect of aprotinin on transfusion requirements during repeat sternotomy for cardiac transplantation surgery. Transplant Proc 1994;26: 3719–21.[Medline]
  14. Havel M, Owen AN, Simon P, et al. Decreasing use of donated blood and reduction of bleeding after orthotopic heart transplantation by use of aprotinin. J Heart Lung Transplant 1992;11:348–9.[Medline]
  15. Rose EA, Barr ML, Xuh H, et al. Photochemotherapy in human heart transplant recipients at high risk for fatal rejection. J Heart Lung Transplant 1992;11:746–50.[Medline]
  16. Goldstein DJ, Seldomridge JA, Chen JM, et al. Use of aprotinin in LVAD recipients reduces blood loss, blood use, and perioperative mortality. Ann Thorac Surg 1995;59:1063–7.[Abstract/Free Full Text]



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